Dalcetrapib for Patients with a Recent Acute Coronary Syndrome

Observational studies have shown an inverse association between levels of high-density lipoprotein (HDL) cholesterol and incident events of coronary heart disease. The association persists in the majority of post hoc analyses and meta-analyses of trials of statin therapy for patients with cardiovascular disease risk factors, chronic cardiovascular disease, or recent acute coronary syndrome.

However, according to researchers, it is not known whether pharmacologic interventions to raise HDL cholesterol levels result in reduction in risks for cardiovascular disease. In addition, the physiologic functions of HDLs may not change with changes in HDL cholesterol levels.

Noting that inhibition of cholesteryl ester transfer protein (CETP) raises HDL levels, the researchers hypothesized that cardiovascular outcomes would be improved with treatment with CETP inhibitors. They conducted the dal-OUTCOMES study to evaluate the effects of dalcetrapib, a CETP inhibitor, on cardiovascular risk among patients with a recent acute coronary syndrome. Trial results were reported at the American Heart Association 2012 Scientific Sessions and online in the New England Journal of Medicine [doi:10.1056/NEJMoa1206797].

The phase 3 trial included 15,871 patients who were randomly assigned to receive dalcetrapib at a dose of 600 mg daily or placebo, plus the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization of unstable angina with objective evidence of acute myocardial ischemia, or cardiac arrest with resuscitation), or ischemic stroke.

Secondary end points were each component of the primary composite end point, unanticipated coronary revascularization (excluding revascularization for restenosis at the previous intervention site), death from any cause, and changes in levels of circulating lipoproteins and inflammatory markers.

The trial was conducted at 935 sites in 27 countries. Of the 15,871 patients meeting inclusion criteria, 87% had elevated cardiac biomarkers at the time of the qualifying event (with the elevation related to percutaneous coronary intervention in 2% of the patients). The median time from the qualifying event to randomization was 61 days.

At baseline, the characteristics of the 2 groups were well matched. Most patients were treated with aspirin, statins, thienopyridines, beta-blockers, and angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, and underwent a coronary revascularization procedure between the time of the qualifying event and randomization.

Mean baseline level of low-density lipoprotein (LDL) cholesterol was 76 mg per deciliter, mean HDL cholesterol level was 42 mg per deciliter, mean apolipoprotein A1 level was 137 mg per deciliter, and mean apolipoprotein B level was 81 mg per deciliter.

During the study period (April 2008 through 2010), HDL cholesterol levels increased from baseline by 4% to 11% in the placebo group and by 31% to 40% in the dalcetrapib group. There was little effect of dalcetrapib on LDL cholesterol levels.

At the second prespecified interim analysis, which included 1135 primary end-point events, the independent data and safety monitoring board recommended termination of the trial for futility. The sponsor and executive steering committee accepted this recommendation and terminated the trial; median follow-up was 31 months.

The researchers provided several possible explanations for the lack of benefit of dalcetrapib treatment. One, there was no association between HDL cholesterol levels and cardiovascular risk among the participants in the trial, including the placebo group. The lack of such an association may be an indication that HDL cholesterol levels are no longer a determinant of risk when patients are treated with the evidence-based therapies that were used by trial participants.

Another possibility raised by the researchers is that HDLs are protective in healthy people who do not have cardiovascular disease, but their composition is altered when cardiovascular disease develops. Thus, the composition and function of HDLs may have been altered adversely following the qualifying acute coronary event.

The researchers concluded by noting that, “In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels, but did not reduce the risk of recurrent cardiovascular events.”